2-hydroxy and 2-carbamyloxy derivatives of 1,1,1-trichloro-3-carbamyloxyalkanes in a composition and method for effecting muscle relaxation

ABSTRACT

1,1,1-Trichloro-2-HYDROXY-3-carbamyloxyalkanes and their 2carbamyloxy derivatives such as 1,1,1-trichloro-2-hydroxy-3carbamyloxypropane, 1,1,1-trichloro-2-hydroxy-3-carbamyloxybutane and 1,1,1-trichloro-2,3-dicarbamyloxybutane are depressants of the central nervous system and useful as muscle relaxants.

United States Patent 91 Darko 1 Mar. 27, 1973 .[75] Inventor: Laszlo L.

[54] Z-HYDROXY AND 2-CARBAMYLOXY DERIVATIVES OF 1,1,1-TRICHLORO-3-CARBAMYLOXYALKANES IN A COMPOSITION AND METHOD FOR EFFECTING MUSCLERELAXATION Darko, Yorktown Heights, N.Y.

[73] Assignee: Ciba-Geigy Corporation, Ardsley,

[22] Filed: June 29, 1970 [21] Appl. No.: 158,112

Related US. Application Data [60] Division of Ser. No. 25,282, April 2,1970, Pat. No. 3,639,453, which is a continuation-in-part of Ser. No.786,750, Dec. 24, l968, abandoned.

[52] US. Cl ..,.....424/300 [51] Int. Cl. ..A61k 27/00 [58] Field ofSearch ..424/300 Primary ExaminerSta.n1ey J. Friedman Attorney-Karl F.Jorda et a1.

57 ABSTRACT 2 Claims, No Drawings Z-IIYDROXY AND Z-CARBAMYLOXYDERIVATIVES OF 1,1,l-TRICIILORO-3- CARBAMYLOXYALKANES IN A COMPOSITIONAND METHOD FOR EFFECTING MUSCLE RELAXATION CROSS REFERENCE This is adivisional of Ser. No. 25,282, filed Apr. 2,

1970, now U.S. Pat. No. 3,639,453, which in turn is a continuation inpart of Ser. No. 786,750, filed Dec. 24, 1968, now abandoned.

DETAILED DESCRIPTION The present invention pertains to a class oforganic compounds, to a process for their preparation and tocompositions and methods for their use. This class of organic compoundscan be characterized as l,1,ltrichloro-2-hydroxy-3-carbamyloxyalkanesand the 2- carbamyloxy derivatives thereof and graphically depicted bythe following structural formula:

OR R 0 wherein R is hydrogen or the group sitis, chorea and the like.Although the amount given toan animal will depend upon its size, speciesresponse, condition, and response desired, generally a dose from about 1to about 50 mg/kg of body weight is employed. The following descriptionof using and making the invention represents the best modes presentlycontemplated for carrying out the invention. When employed as musclerelaxants, the compounds of the present invention are incorporated incompositions suitable for oral administration to animals in solid andliquid unit dosage forms, such as tablets, capsules, powders, granules,syrups, elixirs, and the like. The term unit dosage form as used in thisspecification and claims refers to physically discrete units suitable asunitary dosages for animals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticaldiluent, carrier or vehicle.

Powders are prepared by comminuting a l,1,ltrichloro-3-carbamyloxyalkaneto a suitably fine size and mixing with a similarly comminuted diluent.The diluent can be an edible carbohydrate material such as starch. Asweetening agent or sugar may also be present as well as flavoring oil.

Granules for reconstitution into a liquid oral preparation are preparedutilizing water-soluble diluents. A powder mixture of finely divided1,1,1- trichloro-3-carbamyloxyalkane and a water-soluble diluent such assucrose, glucose, and the like, is wetted with a binder such as acaciamucilage, gelatin solution, methylcellulose solution and forced througha screen to form granules which are allowed to dry. A suspending agentsuch as tragacanth may be included in the composition.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. As an adjuvant to the filling operation,a lubricant such as talc, magnesium stearate and calcium stearate may beaddedto the powder mixture before the filling operation.

, Tablets are made by granulating or slugging a powder mixture asdescribed above, adding a lubricant and pressing into tablets. Thepowder mixture is prepared by mixing the compound, suitably comminuted,with a diluent or base such as starch, sucrose, kaolin, dicalciumphosphate and the like. The powder mixture can be granulated by wettingwith a binder.

such as syrup, starch paste or acacia mucilage and forcing through ascreen or, as an alternative to granulating, the powder mixture is runthrough the tablet machine and the resulting imperfectly formed tabletsbroken into slugs. The slugs may be lubricated to prevent sticking tothe tablet forming dies by means of the addition of a substance such asstearic acid a stearate salt, talc or mineral oil. The lubricatingmixture is then compressed into tablets. A protective coating consistingof a sealing coat of shellac,'a coating of sugar and methylcellulose,and a polish coating of wax such as carnauba may be provided.

Oral fluids are prepared in unit dosage forms such as syrups and elixirswherein each teaspoonful of composition contains a predetermined amountof the compound for administration. A syrup is prepared by suspending al,1,l-trich1oro-3-carbamyloxyalkane-in a suitably flavored aqueoussucrose solution while an elixir is prepared utilizing instead anontoxic alcohol vehicle.

Aqueous and oleaginous fluid unit dosage forms can be prepared forparenteral administration. In preparing the parenteral form, ameasuredamount of the compound is placed in a vial and the vial and itscontents sterilized and sealed. An accompanying vial of sterile watermay be provided as a vehicle to form a suspension prior toadministration.

The compounds of the present invention wherein R is hydrogen areprepared through treatment of a 1,1 ,ltrichloro-2,3-dihydroxyalkane ofFormula II with a carbamyl chloride of Formula 111:

In the foregoing, R, R" and R are as previously defined. The reaction iseasily executed through mixing the two reactants in an inert organicsolvent such as ethyl ether, benzene, toluene, pyridine or the like and,

heating this mixture at temperatures up to about 100 C. Alternativelyphosgene and an amine of the formula:

, which together represent the functional equivalent of the abovecarbamyl chloride of Formula Ill, can be used.

The desired product is isolated through conventional techniques such asconcentration with any unreacted starting material being removed throughsolvent extraction as with water, carbon tetrachloride or the like. Theproduct is purified through recrystallization, chromatography or thelike.

In the case of those compounds of Formula I wherein R is the group a1,1,l-trichloro-2'hydroxy-3-carbamyloxy derivative of Formula I is firsttreated with Grignard reagent. This intermediate isthen treated withphosgene followed by ammonia or an amine of the formula:

least one carbon atom having asymmetric substitution and can thereforebe separated into optical isomers. Moreover when R is other thanhydrogen, isomeric threo and erythro forms are present. These are mostconveniently separated in the synthesis of the starting materials ofFormula II by utilization of their different physical properties, e.g.,through fractional distillation. All such isomeric forms are within thescope of the present invention.

The following Examples will serve to further typify the nature of thepresent invention without being a limitation on the scope thereof.

PREPARATION 1,1 ,-Trichlorobutane-2,3-diol To a suspension of 1.5 molesof mercuric acetate in 1.5 l. of methanol is added 0.5 mole of3-butyn-2-ol. Upon completion of the addition, heat evolves and theformed complex precipitates. The complex is removed by filtration andsuspended in chloroform. Chlorine gas LII is bubbled through thesuspension until refluxing ceases. The reaction mixture is then filteredand the filtrate is washed with 2N hydrochloric acid, saturated sodiumbicarbonate solution, sodium thiosulfate solution and water. The washedsolution is then dried over magnesium sulfate, filtered and evaporatedto a yellow liquid. Distillation at 98 C/8mm yields 1,1,l-trichloro-3-acetoxybutan-2-one.

To 43.5 of lithium aluminum hydride suspended in 2.5 l. of ether areadded over an minute period with vigorous stirring 296.85 g (1.27 mole)of 1,1,1- trichloro-3-acetoxybutan-2-one dissolved in 400 ml ofanhydrous ether. The addition is controlled so that reflux is maintainedat a moderate rate. The reaction mixture is then refluxed for anadditional 24 hours. The excess lithium aluminum hydride is thendestroyed with ethyl acetate and the reaction mixture poured overicecooled solution of diluted acid. The mixture is extracted with etherand the ether extracts are dried over magnesium sulfate, filtered andevaporated. The residue is then fractionally distilled to yield threo1,1,1- trichlorobutane-Z,3-diol, b.p. 72.5 C/1.4 mm and thecorresponding erythro isomer, b.p. 76 C/l .2 mm. The products solidifyand are further purified through recrystallization, from methylenechloride or chloroform, and fractional sublimation, threo isomer, m.p.6263 C, erythro isomer, m.p. 85.587 C.

EXAMPLE 1 1,1 ,l-Trichloro-2-hydroxy-3-carbamyloxypropane To 5.0 g ofcarbamyl chloride suspended in 60 ml of ether is slowly added a solutionof 10.0 g (0.056 mole) of 1,1,l-trichloropropane-2,3-diol in 60 ml ofether. After the addition is complete, the reaction mixture is stirredat reflux temperatures for 3 hours, cooled, evaporated in vacuo andextracted three times with 50 ml of hot benzene. Evaporation of thecombined benzene extracts yields the crude product from which theunreacted starting material is removed by extraction with hot carbontetrachloride. The residue is distilled, b.p. 174/l.0 mm, andcrystallization from benzene yields the pure product, m.p. 66.568.5 C.

Calcd. for C I-I NCl O C, 21.60; H, 2.72; N, 6.29; CI,

Found: 21.40; 2.85; 6.52; 47.24.

EXAMPLE 2 1,1 ,l-Trichloro-2-hydroxy-3-(N,N-dimethylcarbamyloxy)propanoTo a boiling solution of 50 g (0.28 mole) of l,l,ltrichloropropane-2,3-diol in 80 ml of benzene is added a solution of26.8 g (0.25 mole) of dimethylcarbamyl chloride in 50 ml of benzene. Thereaction mixture is heated at reflux temperature for 4 hours, cooled,washed with water, dried over magnesium sulfate and evaporated in vacuoto yield the crude product. Unreacted starting material is removed byextraction with hot water and recrystallization of the residue fromcyclohexane yields the pure compound, m.p. 84.5-8 5.5C. Calcd forc,H,,Nc|,,o C, 28.75; H, 4.02; N, 5.59; CI, 42.47;

Found: 28.58;4.31; 5.32;42.50.

EXAMPLE 3 1,1,1-Trichloro-2-hydroxy-3-(N,N-diethylcarbamyloxy)propane To2.08 g (0.0154 mole) of diethyl carbamyl chloride in ml of ether areadded with stirring 5 g (0.0279 mole) of 1,1,1-trichloropropane-2,3-diolin 30 ml of ether. The resulting solution is heated at refluxtemperature for 2 hours, cooled, treated with 10 ml of 10 percentaqueous sodium hydroxide and extracted 3 times with 25 ml portions ofwater. The organic phase is dried and evaporated to dryness in vacuo.The residual oil solidifies upon standing and is recrystallized fromcarbon tetrachloride to yield the pure product, m.p. 9698 C.

Calcd for C H NCI O C, 34.50; H, 5.00; N, 5.03; Cl,

Found: 34,50; 5.20; 4.95; 38.21.

EXAMPLE 4 Erythro-l ,l,1-trichloro-2-hydroxy-3-(N,N-diethylcarbamyl)butane To 8 g (0.0415) oferythro-l ,1,1-trichlorobutane- 2,3-diol dissolved in 50 ml of drypyridine are added with stirring, 5.42 g (0.04 mole) of diethylcarbamylchloride. The reaction mixture is refluxed for an additional 2 9% hours,cooled to 0 C, acidified with 5N HCl to pH 1 and extracted 3 times with50 ml portions of chloroform. The chloroform extracts are washed withwater, dried and evaporated to dryness in vacuo. High vacuumdistillation yields the product, b.p. 1071 15 /0.1 mm, which solidifiesand is recrystallized from hexane, m.p. 56.557.5 C. Calcd for C H NCI OC, 36.94; H, 5.51, N, 4.78; CI, 36.35:

Found: 36.93;5.43;4.84; 36.33. 4

EXAMPLE 5 Erythro-l ,1,1-trichloro-2-hydroxy-3-carbamyloxybutane To asuspension of 3.5 (0.042 mole) of carbamyl chloride in 25 ml of benzeneis added over a 10 minute period, a warm solution of 5 g (0.0259 mole)of erythro-l,l,1-trichlorobutane-2,3-diol in 50 ml of benzene. Duringthe addition the reaction mixture is heated to 60 C. After addition iscompleted, the reaction mixture is stirred at reflux temperature for anadditional 3 hours. The hot solution is filtered and evaporated todryness. The residue is recrystallized several times from benzene andsublimated in vacuo to yield pure erythro1,1,1-trichloro-2-hydroxy-3-carbamyloxybutane, m.p. 108l10.5 C. Calcdfor C,H NCI O,: C, 25.40; H, 3.41; N, 5.92; CI, 44.7;

Found: 25.37; 3,38; 5,67; 44.70.

EXAMPLE 6Erythro-1,1,1-trichloro-2-hydroxy-3-(N,N-dimethylcarbamyloxy)butane To asolution of 20.0 g (0.014 mole) of erythro 1,1,1-trichlorobutane-2,3-diol in 45 ml of benzene at are added slowly withstirring, 10.7 g (0.1 mole) of dimethylcarbamyl chloride in 25 m1 ofbenzene. The reaction mixture is refluxed for an additional 12 hours.

After cooling, the benzene solution is washed with water, dried andevaporated to dryness in vacuo to yield the crude product, m.p. 106.Recrystallization of this solid from carbon tetrachloride raises themelting point to -l1l C.

Calcd. for C H NCI O C, 31.78; H, 4.57; N, 5.29; Cl, 40.21;

Found: 31.70; 4.69; 5.25; 40.52.

EXAMPLE 7 Threo 1,1,1-Trichloro-2-hydroxy-3-carbamyloxybutane To asuspension of 12.7 g (0.16 mole) of carbamyl chloride in 100 ml ofbenzene is added over 10 minutes to a solution of 17.6 g (0.091 mole) ofthreo 1,1,1- trichlorobutane-2,3-diol in 60 ml of warm benzene. Afterthe addition is complete, the reaction mixture is stirred at reflux for3 hours, cooled and filtered. The filtrate is evaporated in vacuo. Highvacuum distillation of the residue yields the product, b.p. 150/0.3 mm,which solidifies and is recrystallized from methylene chloride andsublimated to yield the pure product, m.p. 107-108.5. Calcd. for C H NClO C, 25.40; H, 3.41; N, 5.92; Cl,

Found: 25.52; 3.17; 6.20; 44.83.

EXAMPLE 8 1,1,1Trichloro-2,3-dicarbamyloxypropane To 15 ml of 1.7 Mmethylmagnesium chloride in ether are added over a 15 minute period, 1.9g (0.0086 mole) of l,1,1-trichloro-2-hydroxy-3-carbamyloxypropane in 15ml of ether. Stirring at reflux is continued for 30 minutes and thereaction mixture is then cooled and 20 ml of a 12.5 percent solution ofphosgene in benzene are added. Refluxing is resumed for an additional 30minutes and ammonia gas is then passed into the cooled reaction mixturefor 45 minutes. The solid which forms is removed by filtration and thefiltrate is evaporated to dryness. Recrystallization of the residue frombenzene-ethanol yields the pure product, m.p. 128131C.

Calcd. for C H N Cl O.,: C, 22.63; H, 2.66; N, 10.56; C], 40.07

Found: 22.46; 2.85; 10.28; 40.23.

In a similar fashion, by utilizing 1,1,1-trichloro-2-hydroxy-3-(N,N-diethylcarbamyloxy)propane in the above procedure thereis obtained 1,1,1-trichloro-2-carbamyloxy-3-(N,N-diethylcarbamyloxy)propane.

EXAMPLE 9 Erythro-l,1,1-Trichloro-2,3-dicarbamyloxybutane To a solutionof 10.4 g (0.04 moles) of 1,1,1- trichloro-2-hydroxy-3-carbamyloxybutanein 100 ml of anhydrous ether, cooled in an ice-water bath, are added 25ml of 1.8 M ethereal methylmagnesium chloride. After the addition iscomplete, the reaction mixture is heated at reflux for 30 minutes andcooled.

35 milliliters of a 12.5 percent solution of phosgene inv benzene areadded with stirring and the reaction mixture is then stirred, at refluxfor 30 minutes and at room temperature for an additional 15 minutes.Though the cooled solution is bubbled anhydrous ammonia. The resultingsolid is separated, suspended in water and extracted 3 times with 150portions of ether. The combined extracts are dried over magnesiumsulfate, filtered and evaporated in vacuo to yield a white solid.Recrystallization from chloroform yields the pure product, m.p.198.5200.5.

Calcd. for C H N Cl O C, 25.78; H, 3.25; N, 10.02; Cl, 38.06;

Found: 25.89',3.10;9.83; 37.73.

Similarly from erythro 1,1,1-trichloro-2-hydroxy-3-(N,N-dimethylcarbamyloxy)butane there is obtained erythro 1,1 1-trichloro-Z-carbamyloxy-3-(N,N- dimethylcarbamyloxy)-butane.

EXAMPLE l Threo-1,1,l-trichloro-2,3-dicarbamyloxybutane To a solution of3.0 g (0.01 moles) of threo-l,1,ltrichloro-2-hydroxy-3-carbamyloxybutanein 30 ml of anhydrous ether, cooled in an ice-water bath, are added 7.2ml of 1.8 M ethereal methylmagnesium chloride. After the addition iscomplete the reaction mixture is stirred at reflux temperature for 30minutes and cooled and 10.1 ml of a 12.5 percent solution of phosgene inbenzene are added. After this addition is complete, the reaction mixtureis stirred at reflux temperature for 30 minutes and then at roomtemperature for an additional minutes. It is cooled and anhydrousammonia is next bubbled into the reaction vessel. The reaction mixtureis then suspended in 50 ml of water and extracted 4 times with 50 mlportions of ether. The combined extracts are dried over magnesiumsulfate, filtered and evaporated to dryness to yield the product whichis recrystallized from 500 ml of chloroform, m.p. 200202 C. Calcd. for C11,,N C1 O C, 25.78; H, 3.25; N, 10.02; Cl, 38.06;

Found: 25.77; 2.97;9.99; 38.13.

EX AM PLE l 1 Ingredients Quantity/Capsule Threo-l ,1,1-trichlor0-2hydroxy- 3-carbamyloxybutane 200 mg Cum Starch U.S.P. 200mg The foregoing ingredients are mixed thoroughly and introduced into atwo-piece No. 1 hard gelatin capsule.

EXAMPLE 12 Ingredients Quantity/Tablet 1,1,1-trichloro-2-hydroxy-3-(N,N-diethylcarbamyloxy)propane 250 mg Corn Starch U.S.P. mg Lactose mgCab-O-Sil M-5 4 mg Gelatin U.S.P. 5 mg Magnesium Stearate U.S.P. 1 mgThe foregoing ingredients are thoroughly mixed andwherein R is hydrogenor the group and each of R, R R R and R independent of the other, ishydrogen or (lower)alkyl and a pharmaceutical carrier.

2. The method of effecting muscle relaxation in an animal whichcomprises administering thereto an effective amount of a compositionaccording to claim 1.

2. The method of effecting muscle relaxation in an animal whichcomprises administering thereto an effective amount of a compositionaccording to claim 1.